DESCRIPTION (provided by candidate): The goal of this project is to determine the influence of sex and gonadal hormones on the susceptibility of the circadian system to methamphetamine. Methamphetamine dramatically alters circadian rhythms;methamphetamine lengthens the free-running period of mice and can reinstate rhythmicity in otherwise arrhythmic animals. C3H mice exhibit a clear sex difference in the response of their circadian systems to methamphetamine. The first aim of this project will be to test the hypothesis that gonadal steroids affect the ability of methamphetamine to alter circadian locomotor activity patterns. To accomplish this aim, methamphetamine will be given to intact, gonadectomized, and hormone-replaced male and female mice, and the effect on the circadian rhythm of wheel-running will be measured. In order to determine if there is also an organizational effect of perinatal hormone exposure on sensitivity to methamphetamine, we will test the effects of methamphetamine in adulthood on the circadian systems of neonatally androgenized mice. The second aim of this research will be to test the interaction of methamphetamine and gonadal steroid background on the phase and period of circadian oscillators in individual tissues. Using both male and female mice with a PERIOD2::LUCIFERASE reporter, we will examine the effects of methamphetamine on circadian oscillations in the brain, liver, and kidney. Circadian rhythms impact every major system in the body, with independent oscillators keeping time in almost every cell. The influence of methamphetamine on the circadian system is therefore likely to give rise to a host of physiological and health-related problems. Research on the influence of sex and gonadal steroids in the response to psychostimulants has the potential to provide a framework for developing treatment and prevention strategies for methamphetamine users, particularly the at-risk female population.